tbuckley/cabot-search huggingface dataset:
Normalization of cerebral hemodynamics after hematopoietic stem cell transplant in children with sickle cell disease
Authors: Monica L. Hulbert, Melanie E. Fields, Kristin P. Guilliams, Priyesha Bijlani, Shalini Shenoy, Slim Fellah, Alison S. Towerman, Michael M. Binkley, Robert C. McKinstry, Joshua S. Shimony, Yasheng Chen, Cihat Eldeniz, Dustin K. Ragan, Katie Vo, Hongyu An, Jin-Moo Lee, Andria L. Ford
Journal: Blood (2022)
Errors in the Supplement
Journal: JAMA Network Open (2022)

Kang Liu, MS; Xiangzhou Zhang, PhD; Weiqi Chen, PhD; Alan S. L. Yu, MB, BChir; John A. Kellum, MD, MCCM; Michael E. Matheny, MD, MS, MPH; Steven Q. Simpson, MD; Yong Hu, PhD; Mei Liu, PhD
CD39/CD73 dysregulation and adenosine metabolism contribute to T-cell immunosuppression in patients with Sézary syndrome
Authors: Yuliya Yakymiv, Sara Marchisio, Erika Ortolan, Cristiano Bracci, Rebecca Senetta, Maria Rebecca Rumore, Cristian Tampieri, Marianna Fia, Simone Ribero, Ada Funaro, Pietro Quaglino
Journal: Blood (2022)
Clinico-genomic Characterization of<i>ATM</i>and HRD in Pancreas Cancer: Application for Practice
Authors: Wungki Park, Catherine A. O'Connor, Chaitanya Bandlamudi, Daniella Forman, Joanne F. Chou, Shigeaki Umeda, Marsha Reyngold, Anna M. Varghese, Fergus Keane, Fiyinfolu Balogun, Kenneth H. Yu, David P. Kelsen, Christopher Crane, Marinela Capanu, Christine Iacobuzio-Donahue, Eileen M. O'Reilly
Journal: Clinical Cancer Research (2022)

Characterizing germline and somatic ATM variants (gATMm, sATMm) zygosity and their contribution to homologous recombination deficiency (HRD) is important for therapeutic strategy in pancreatic ductal adenocarcinoma (PDAC).
Conformation of von Willebrand factor in shear flow revealed with stroboscopic single-molecule imaging
Authors: Hans T. Bergal, Yan Jiang, Darren Yang, Timothy A. Springer, Wesley P. Wong
Journal: Blood (2022)

von Willebrand factor (VWF) is a multimeric blood protein that acts as a mechanical probe, responding to changes in flow to initiate platelet plug formation. Previously, our laboratory tests had shown that using single-molecule imaging that shear stress can extend surface-tethered VWF, but paradoxically, we found that the required shear stress was higher than reported for free-in-flow VWF, an observation inconsistent with basic physical principles. To resolve this inconsistency critical to VWF's molecular mechanism, we measured free-VWF extension in shear flow using pulsed laser stroboscopic imaging of single molecules. Here, laser pulses of different durations are used to capture multiple images of the same molecule within each frame, enabling accurate length measurements in the presence of motion blur. At high shear stresses, we observed a mean shift in VWF extension of <200 nm, much shorter than the multiple-micron extensions previously reported with no evidence for the predicted sharp globule-stretch conformational transition. Modeling VWF with a Brownian dynamics simulation, our results were consistent with VWF behaving as an uncollapsed polymer rather than the theorized compact ball. The muted response of free VWF to high shear rates implies that the tension experienced by free VWF in physiological shear flow is lower than indicated by previous reports and that tethering to platelets or the vessel wall is required to mechanically activate VWF adhesive function for primary hemostasis.
Availability of New Medicines in the US and Germany From 2004 to 2018
Authors: Katharina Blankart, Huseyin Naci, Amitabh Chandra
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Germany's unique approach to coverage determination and pricing has ensured that effective medicines remain on the market, often at prices reduced through negotiation. However, less is known about trade-offs of this approach with regard to initial availability of medicines. <h3>Objective</h3> To examine differences in the timing and scope of new medicines available in Germany and the US. <h3>Design, Setting, and Participants</h3> This retrospective cohort study analyzed initial availability of new medicines approved by regulatory agencies in Germany and the US between January 1, 2004, and December 31, 2018, and followed up through December 31, 2019. Data analysis was conducted from January 1, 2020, to July 1, 2022. A total of 599 novel approvals were reviewed. Generic, biosimilar, vaccine, and combination medicines were excluded. <h3>Exposures</h3> US Food and Drug Administration approvals were reviewed for therapies categorized as new molecular entities or new active ingredients. German approvals were reviewed from secondary administrative data of authorized medicines that determine availability in Germany, including data presented by the European Medicines Agency. <h3>Main Outcomes and Measures</h3> Approvals were analyzed to determine the percentage of medicines approved and available in the US, Germany, or both countries and compare the times to reach the market. <h3>Results</h3> Analysis of 599 new medicines demonstrated that fewer were available in Germany compared with the US (80% vs 92% of all potential therapies) and that the median difference in time to market was 4 months (95% CI, −44.40 to 44.76 months). Forty-nine medicines were approved in Germany but not in the US, 75% of which were rejected by the US Food and Drug Administration, were withdrawn, or had US equivalent agents. <h3>Conclusions and Relevance</h3> In this cohort study, fewer new medicines were available in Germany compared with the US between 2004 and 2018. In addition, drugs entered the German market later than in the US.
Delayed Increase in Abusive Head Trauma in Paris During COVID-19 Pandemic
Authors: Emily C. B. Brown
Journal: JAMA Network Open (2022)

Alina-Marilena Lãzãrescu, MD; Sandro Benichi, MD; Thomas Blauwblomme, MD, PhD; Kévin Beccaria, MD, PhD; Marie Bourgeois, MD; Charles-Joris Roux, MD; Estelle Vergnaud, MD; Juliette Montmayeur, MD; Philippe Meyer, MD; Jérémie F. Cohen, MD, PhD; Martin Chalumeau, MD, PhD; Flora Blangis, MPH; Gilles Orliaguet, MD, PhD
Herpes Simplex Encephalitis in a Patient With Lymphoma
Authors: Alan L. Rothman
Journal: JAMA (1988)

HERPES simplex encephalitis (HSE) is the most common cause of fatal sporadic encephalitis.<sup>1</sup>Recognition of this entity has become increasingly important with the advent of effective antiviral therapy. Clinical studies with vidarabine, and then with acyclovir sodium, See also pp 1051,1054, and 1067. treatment have supported a ten-day course of therapy as the standard duration. We recently cared for a patient who calls into question the adequacy of this regimen for the immunocompromised patient. <h3>Report of a Case</h3> A 58-year-old right-handed man presented in October 1986 with a one-day history of fever, confusion, and speech difficulty. Eighteen months previously he had been diagnosed with stage III, diffuse, poorly differentiated lymphocytic lymphoma; he had received chemotherapy, with minimal response, until six months before this hospitalization. On admission, his temperature was 38.6°C. The patient was disoriented to place and time; he was able to follow simple commands, but recall was poor.
Innate type 2 immunity controls hair follicle commensalism by Demodex mites
Authors: Roberto R. Ricardo-Gonzalez, Maya E. Kotas, Claire E. O’Leary, Katelyn Singh, William Damsky, Chang Liao, Elizabeth Arouge, Iliana Tenvooren, Diana M. Marquez, Andrew W. Schroeder, Jarish N. Cohen, Marlys S. Fassett, Jinwoo Lee, Scott G. Daniel, Kyle Bittinger, Roberto Efraín Díaz, James S. Fraser, Niwa Ali, K. Mark Ansel, Matthew H. Spitzer, Hong-Erh Liang, Richard M. Locksley
Journal: Immunity (2022)

Demodex mites are commensal parasites of hair follicles (HFs). Normally asymptomatic, inflammatory outgrowth of mites can accompany malnutrition, immune dysfunction, and aging, but mechanisms restricting Demodex outgrowth are not defined. Here, we show that control of mite HF colonization in mice required group 2 innate lymphoid cells (ILC2s), interleukin-13 (IL-13), and its receptor, IL-4Ra-IL-13Ra1. HF-associated ILC2s elaborated IL-13 that attenuated HFs and epithelial proliferation at anagen onset; in their absence, Demodex colonization led to increased epithelial proliferation and replacement of gene programs for repair by aberrant inflammation, leading to the loss of barrier function and HF exhaustion. Humans with rhinophymatous acne rosacea, an inflammatory condition associated with Demodex, had increased HF inflammation with decreased type 2 cytokines, consistent with the inverse relationship seen in mice. Our studies uncover a key role for skin ILC2s and IL-13, which comprise an immune checkpoint that sustains cutaneous integrity and restricts pathologic infestation by colonizing HF mites.
A “multi-omics” analysis of blood–brain barrier and synaptic dysfunction in <i>APOE4</i> mice
Authors: Giuseppe Barisano, Kassandra Kisler, Brent Wilkinson, Angeliki Maria Nikolakopoulou, Abhay P. Sagare, Yaoming Wang, William Gilliam, Mikko T. Huuskonen, Shu-Ting Hung, Justin K. Ichida, Fan Gao, Marcelo P. Coba, Berislav V. Zlokovic
Journal: The Journal of Experimental Medicine (2022)

Apolipoprotein E4 (APOE4), the main susceptibility gene for Alzheimer’s disease, leads to blood–brain barrier (BBB) breakdown in humans and mice. Remarkably, BBB dysfunction predicts cognitive decline and precedes synaptic deficits in APOE4 human carriers. How APOE4 affects BBB and synaptic function at a molecular level, however, remains elusive. Using single-nucleus RNA-sequencing and phosphoproteome and proteome analysis, we show that APOE4 compared with APOE3 leads to an early disruption of the BBB transcriptome in 2–3-mo-old APOE4 knock-in mice, followed by dysregulation in protein signaling networks controlling cell junctions, cytoskeleton, clathrin-mediated transport, and translation in brain endothelium, as well as transcription and RNA splicing suggestive of DNA damage in pericytes. Changes in BBB signaling mechanisms paralleled an early, progressive BBB breakdown and loss of pericytes, which preceded postsynaptic interactome disruption and behavioral deficits that developed 2–5 mo later. Thus, dysregulated signaling mechanisms in endothelium and pericytes in APOE4 mice reflect a molecular signature of a progressive BBB failure preceding changes in synaptic function and behavior.
Pan-Cancer Analysis of Canonical and Modified miRNAs Enhances the Resolution of the Functional miRNAome in Cancer
Authors: Rosario Distefano, Luisa Tomasello, Gian Luca Rampioni Vinciguerra, Pierluigi Gasparini, Yujia Xiang, Marina Bagnoli, Gioacchino P. Marceca, Paolo Fadda, Alessandro Laganà, Mario Acunzo, Qin Ma, Giovanni Nigita, Carlo M. Croce
Journal: Cancer Research (2022)

Abstract Epitranscriptomic studies of miRNAs have added a new layer of complexity to the cancer field. Although there is fast-growing interest in adenosine-to-inosine (A-to-I) miRNA editing and alternative cleavage that shifts miRNA isoforms, simultaneous evaluation of both modifications in cancer is still missing. Here, we concurrently profiled multiple miRNA modification types, including A-to-I miRNA editing and shifted miRNA isoforms, in &amp;gt;13,000 adult and pediatric tumor samples across 38 distinct cancer cohorts from The Cancer Genome Atlas and The Therapeutically Applicable Research to Generate Effective Treatments data sets. The differences between canonical miRNAs and the wider miRNAome in terms of expression, clustering, dysregulation, and prognostic standpoint were investigated. The combination of canonical miRNAs and modified miRNAs boosted the quality of clustering results, outlining unique clinicopathologic features among cohorts. Certain modified miRNAs showed opposite expression from their canonical counterparts in cancer, potentially impacting their targets and function. Finally, a shifted and edited miRNA isoform was experimentally validated to directly bind and suppress a unique target. These findings outline the importance of going beyond the well-established paradigm of one mature miRNA per miRNA arm to elucidate novel mechanisms related to cancer progression. Significance: Modified miRNAs may act as cancer biomarkers and function as allies or antagonists of their canonical counterparts in gene regulation, suggesting the concurrent consideration of canonical and modified miRNAs can boost patient stratification.
High-Resolution Profiling of Lung Adenocarcinoma Identifies Expression Subtypes with Specific Biomarkers and Clinically Relevant Vulnerabilities
Authors: Whijae Roh, Yifat Geffen, Hongui Cha, Mendy Miller, Shankara Anand, Jaegil Kim, David I. Heiman, Justin F. Gainor, Peter W. Laird, Andrew D. Cherniack, Chan-Young Ock, Se-Hoon Lee, Gad Getz
Journal: Cancer Research (2022)

Lung adenocarcinoma (LUAD) is one of the most common cancer types and has various treatment options. Better biomarkers to predict therapeutic response are needed to guide choice of treatment modality and to improve precision medicine. Here, we used a consensus hierarchical clustering approach on 509 LUAD cases from The Cancer Genome Atlas to identify five robust LUAD expression subtypes. Genomic and proteomic data from patient samples and cell lines was then integrated to help define biomarkers of response to targeted therapies and immunotherapies. This approach defined subtypes with unique proteogenomic and dependency profiles. Subtype 4 (S4)-associated cell lines exhibited specific vulnerability to loss of CDK6 and CDK6-cyclin D3 complex gene (CCND3). Subtype 3 (S3) was characterized by dependency on CDK4, immune-related expression patterns, and altered MET signaling. Experimental validation showed that S3-associated cell lines responded to MET inhibitors, leading to increased expression of programmed death-ligand 1 (PD-L1). In an independent real-world patient dataset, patients with S3 tumors were enriched with responders to immune checkpoint blockade. Genomic features in S3 and S4 were further identified as biomarkers for enabling clinical diagnosis of these subtypes. Overall, our consensus hierarchical clustering approach identified robust tumor expression subtypes, and our subsequent integrative analysis of genomics, proteomics, and CRISPR screening data revealed subtype-specific biology and vulnerabilities. These LUAD expression subtypes and their biomarkers could help identify patients likely to respond to CDK4/6, MET, or PD-L1 inhibitors, potentially improving patient outcome.Integrative analysis of multiomic and drug dependency data uncovers robust lung adenocarcinoma expression subtypes with unique therapeutic vulnerabilities and subtype-specific biomarkers of response.
Therapeutic Targeting of Tumor-Infiltrating Regulatory T Cells in Breast Cancer
Authors: Stephane Fattori, Hugo Roux, Emilie Connen, Lucie Robert, Laurent Gorvel, Aude Le Roy, Jemila Houacine, Arnaud Foussat, Anne-Sophie Chretien, Daniel Olive
Journal: Cancer Research (2022)

Abstract Regulatory T cells (Treg) are an immunosuppressive subtype of CD4+ T cells essential for maintaining self-tolerance in physiological settings. Tregs also abundantly infiltrate inflamed tumor tissues, impeding the host's antitumor immune response and contributing to tumor growth and metastasis. In breast cancers, subsets of Tregs express highly immunosuppressive effector phenotypes that favor tumorigenesis, progression, and resistance to immune-checkpoint inhibitor therapies. Tregs share phenotypic features with cytotoxic lymphocytes, rendering them difficult to inhibit without compromising productive antitumor immunity. In addition, systemic targeting of Tregs causes serious autoimmune adverse events in patients with cancer. Hence, the identification of candidate targets or methodologies allowing the specific elimination of tumor antigen-specific Tregs, including tumor-infiltrating Tregs, is a prerequisite for developing efficient and safe combinatorial immunotherapeutic strategies in breast cancers. To date, numerous preclinical studies have demonstrated that specific targeting of breast tumor–infiltrating Tregs restores a competent antitumor immune response and improves responses to immune-checkpoint inhibitors such as PD-1/PD-L1 blockade. Herein, we discuss major candidate molecules for Treg-targeted therapeutic strategies in breast cancers, detailing the pros and cons of various approaches, including mAb-mediated depletion, homeostasis destabilization, and functional blockade.
Scientific and regulatory activities initiated by the U.S. food and drug administration to foster approvals of generic dry powder inhalers: Quality perspective
Authors: Nashwa El-Gendy, Craig M. Bertha, Mohammed Abd El-Shafy, Dhaval K. Gaglani, Andrew Babiskin, Elizabeth Bielski, Susan Boc, Sneha Dhapare, Lanyan Fang, Katharine Feibus, Anubhav Kaviratna, Bing V. Li, Markham C. Luke, Tian Ma, Bryan Newman, Michael Spagnola, Ross L. Walenga, Liang Zhao
Journal: Advanced Drug Delivery Reviews (2022)
Gout: diagnosis and management—summary of NICE guidance
Authors: Julie Neilson, Alexandra Bonnon, Alastair Dickson, Edward Roddy
Journal: BMJ (2022)

### What you need to know Gout is a painful and debilitating condition with long term complications, including joint damage and renal stones. Although gout flares are often treated with NSAIDs, colchicine or steroids, those with gout often continue to have flares which could have been prevented with lifestyle modification or urate lowering medication. However, only a third of people with gout receive urate lowering therapies (ULTs), and only a third of those have their serum urate level managed effectively.1 This article summarises the recommendations from the new National Institute for Health and Care Excellence (NICE) guideline, focusing on the diagnosis and management of gout.2 NICE recommendations are based on systematic reviews of best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on the Guideline Committee's experience and opinion of what constitutes good practice. Evidence levels for the recommendations are given in italic in square brackets. ### Diagnosis and assessment Most people with gout receive a clinical diagnosis in primary care, which is then confirmed by clinical investigation. #### Signs and symptoms
Nintedanib in children and adolescents with fibrosing interstitial lung diseases
Authors: Robin Deterding, Lisa R. Young, Emily M. DeBoer, David Warburton, Steven Cunningham, Nicolaus Schwerk, Kevin R. Flaherty, Kevin K. Brown, Mihaela Dumistracel, Elvira Erhardt, Julia Bertulis, Martina Gahlemann, Susanne Stowasser, Matthias Griese
Journal: European Respiratory Journal (2022)

Childhood interstitial lung disease (ILD) comprises a spectrum of rare ILDs affecting infants, children and adolescents. Nintedanib is a licensed treatment for pulmonary fibrosis in adults. The primary objectives of the InPedILD trial were to determine the dose-exposure and safety of nintedanib in children and adolescents with fibrosing ILD.Patients aged 6-17 years with fibrosing ILD on high-resolution computed tomography and clinically significant disease were randomised 2:1 to receive nintedanib or placebo for 24 weeks and then open-label nintedanib. Dosing was based on weight-dependent allometric scaling. Co-primary end-points were the area under the plasma concentration-time curve at steady state (AUCτ,ss) at weeks 2 and 26 and the proportion of patients with treatment-emergent adverse events at week 24.26 patients received nintedanib and 13 patients received placebo. The geometric mean (geometric coefficient of variation) AUCτ,ss for nintedanib was 175 µg·h·L-1 (85.1%) in patients aged 6-11 years and 160 µg·h·L-1 (82.7%) in patients aged 12-17 years. In the double-blind period, adverse events were reported in 84.6% of patients in each treatment group. Two patients discontinued nintedanib due to adverse events. Diarrhoea was reported in 38.5% and 15.4% of the nintedanib and placebo groups, respectively. Adjusted mean±se changes in percentage predicted forced vital capacity at week 24 were 0.3±1.3% in the nintedanib group and -0.9±1.8% in the placebo group.In children and adolescents with fibrosing ILD, a weight-based dosing regimen resulted in exposure to nintedanib similar to adults and an acceptable safety profile. These data provide a scientific basis for the use of nintedanib in this patient population.
Sotatercept for the treatment of pulmonary arterial hypertension: PULSAR open-label extension
Authors: Marc Humbert, Vallerie McLaughlin, J. Simon R. Gibbs, Mardi Gomberg-Maitland, Marius M. Hoeper, Ioana R. Preston, Rogerio Souza, Aaron B. Waxman, Hossein-Ardeschir Ghofrani, Pilar Escribano Subias, Jeremy Feldman, Gisela Meyer, David Montani, Karen M. Olsson, Solaiappan Manimaran, Janethe de Oliveira Pena, David B. Badesch
Journal: European Respiratory Journal (2022)

In participants with pulmonary arterial hypertension, 24 weeks of sotatercept resulted in a significantly greater reduction from baseline in pulmonary vascular resistance than placebo. This report characterises the longer-term safety and efficacy of sotatercept in the PULSAR open-label extension. We report cumulative safety, and efficacy at months 18-24, for all participants treated with sotatercept.PULSAR was a phase 2, randomised, double-blind, placebo-controlled study followed by an open-label extension, which evaluated sotatercept on top of background pulmonary arterial hypertension therapy in adults. Participants originally randomised to placebo were re-randomised 1:1 to sotatercept 0.3 or 0.7 mg·kg-1 (placebo-crossed group); those initially randomised to sotatercept continued the same sotatercept dose (continued-sotatercept group). Safety was evaluated in all participants who received ≥1 dose of sotatercept. The primary efficacy endpoint was change from baseline to months 18-24 in pulmonary vascular resistance. Secondary endpoints included 6-min walk distance and functional class. Two prespecified analyses, placebo-crossed and delayed-start, evaluated efficacy irrespective of dose.Of 106 participants enrolled in the PULSAR study, 97 continued into the extension period. Serious treatment-emergent adverse events were reported in 32 (30.8%) participants; 10 (9.6%) reported treatment-emergent adverse events leading to study discontinuation. Three (2.9%) participants died, none considered related to study drug. The placebo-crossed group demonstrated significant improvement across primary and secondary endpoints and clinical efficacy was maintained in the continued-sotatercept group.These results support the longer-term safety and durability of clinical benefit of sotatercept for pulmonary arterial hypertension.
Target trial emulation: applying principles of randomised trials to observational studies
Authors: Anthony A Matthews, Goodarz Danaei, Nazrul Islam, Tobias Kurth
Journal: BMJ (2022)

The randomised trial is the preferred study design for evaluating the effectiveness and safety of interventions. Yet such trials can be prohibitively expensive, unethical, or take too long. When it is not possible to carry out a randomised trial, observational data can be used to answer similar questions. Here, we describe the process of using observational data to emulate a target trial, which applies the study design principles of randomised trials to observational studies that aim to estimate the causal effect of an intervention. The target trial provides a formal framework to help avoid self-inflicted biases common to observational studies.